Bald thigh syndrome in sighthounds—Revisiting the cause of a well-known disease

Abstract

Bald thigh syndrome is a common hair loss disorder in sighthounds. Numerous possible causes, including environmental conditions, trauma, stress, endocrinopathies and genetic components have been proposed, but only endocrinopathies have been ruled out scientifically. The overall goal of our study was to identify the cause of bald thigh syndrome and the pathological changes associated with it. We approached this aim by comparing skin biopsies and hair shafts of affected and control dogs microscopically as well as by applying high-throughput technologies such as genomics, transcriptomics and proteomics. While the histology is rather unspecific in most cases, trichogram analysis and scanning electron microscopy revealed severe structural abnormalities in hair shafts of affected dogs. This finding is supported by the results of the transcriptomic and proteomic profiling where genes and proteins important for differentiation of the inner root sheath and the assembly of a proper hair shaft were downregulated. Transcriptome profiling revealed a downregulation of genes encoding 23 hair shaft keratins and 51 keratin associated proteins, as well as desmosomal cadherins and several actors of the BMP signaling pathway which is important for hair shaft differentiation. The lower expression of keratin 71 and desmocollin 2 on the mRNA level in skin biopsies corresponded with a decreased protein expression in the hair shafts of affected dogs. The genetic analysis revealed a missense variant in the IGFBP5 gene homozygous in all available Greyhounds and other sighthounds. Further research is required to clarify whether the IGFBP5 variant represents a predisposing genetic risk factor. We conclude from our results that structural defects in the hair shafts are the cause for this well-known disease and these defects are associated with a downregulation of genes and proteins essential for hair shaft formation. Our data add important knowledge to further understand the molecular mechanisms of HF morphogenesis and alopecia in dogs.

Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs

“…Among the most common variants were several variants with a suggested ancient origin and established distribution across a wide range of modern-day breeds, such as chondrodystrophy and intervertebral disc disease (CDDY), degenerative myelopathy (DM), progressive rod-cone degeneration (prcd-PRA), hyperuricosuria (HUU) and collie eye anomaly (CEA) (12–16). On the other hand, we observed a high frequency of several variants that have so far been linked to specific disease phenotypes based on examinations of a single breed or subpopulation within a breed including IGFBP5 gene candidate variant for bald thigh syndrome in sighthounds (17), SLC7A9 and SLC3A1 gene variants associated with cystinuria in Bulldogs (18, 19), as well as PDK4 and TTN gene risk variants for dilated cardiomyopathy (DCM) in Dobermans (20–22). The clinical impact of these broadly distributed putative genetic risk factors in dogs of a diverse genetic ancestry background were further assessed with the use of electronic medical records.…”

Transcriptome Profiling and Differential Gene Expression in Canine Microdissected Anagen and Telogen Hair Follicles and Interfollicular Epidermis

“…RNA for transcriptome sequencing was extracted from the 20 pooled microdissected HF of the same cycle stage and the IFE collected from each dog. RNA extraction, library preparation and RNA-seq were performed as described in a previous study [ 17 , 36 ]. In brief, total RNA was extracted using the RNeasy Micro Kit (Qiagen, Hombrechtikon, Switzerland) including proteinase K digestion according to the manufacturer’s protocol.…”

“…Low quality bases (−q 15) and illumina adaptors were trimmed with fastp (PMID: 30423086). All reads that passed quality control were mapped with an average of 90% uniquely mapped reads to the dog reference genome (Can.Fam3.1) by STAR aligner version 2.6.0 [ 52 ] as described in a previous study [ 17 , 36 ]. The read abundance was calculated using HTseq and a gtf file (version 105, downloaded and modified in March 2019) obtained from NCBI Can.Fam3.1 annotation release 105 [ 53 ].…”

“…The transcriptome sequencing of skin biopsies in dogs to identify disease phenotypes revealed numerous deregulated genes, some of which are well known and whose expression can thus be associated with a specific location. However, many of the expressed genes have neither been associated with disease nor attributed to a specific tissue or cell type [ 17 , 36 ]. Studies based on the transcriptome profiling of murine epidermis and HFs [ 37 ] and human skin [ 38 , 39 , 40 ] are available.…”

Genetic prevalence and clinical relevance of canine Mendelian disease variants in over one million dogs

“…We also observed several variants that had only previously been associated with disease in a single breed or sub-population, at high frequency across many breeds. This includes the IGFBP5 gene candidate variant for bald thigh syndrome in sighthounds [22], SLC7A9 and SLC3A1 gene variants associated with cystinuria in Bulldogs [23,24], as well as PDK4 and TTN gene risk variants for dilated cardiomyopathy (DCM) in Dobermans [25][26][27]. The clinical impact of these broadly distributed putative genetic risk factors in dogs of a diverse genetic ancestry background were further assessed with the use of electronic medical records.…”